Because lipopolysaccharide (LPS; endotoxin), a component of the outer cell membrane of Gram-negative bacteria, is released into the circulation and is a pathogenic toxin, LPS-reactive monoclonal antibodies are being investigated for treatment of septic shock. In a previous study, we examined the effects of a core/lipid A and O-side chain LPS-reactive monoclonal antibodies and their interaction with antibiotic treatment in a canine model that simulates the serial cardiovascular changes of human septic shock. We found that these two antibodies bacteremia and endotoxemia and prolonged survival. The core/lipid A reactive antibody produced improved hemodynamics. We began an investigation of HA-1A, a human lipid-A reactive monoclonal antibody in a similarly designed study. This antibody had been previously reported to improve survival in a subgroup of patients with gram-negative bacteremia. We found in contrast to the previously investigated lipid A reactive antibody, HA-1A decreased survival in the canine model and was associated with worse sepsis. This result suggests that there may be subgroups of humans with sepsis that are prone to harmful effects of HA-1A. Because anti-endotoxin therapies are now in clinical trials, we plan further investigations that define the pathogenic role of endotoxin in bacterial septic shock.